John W. Fenton II
American · Pharmacology
American thrombin biochemist whose 1986 account of thrombin's active-site regions explained how hirudin blocks both the enzymatic and the receptor-mediated activities of the enzyme.
Profile
- Nationality
- American
- Era
- Late 20th century
- Primary field
- Pharmacology
Key Contributions
- First author, with D. H. Bing, of 'Thrombin active-site regions' in Seminars in Thrombosis and Hemostasis (1986), surveying how the topographic features of α-thrombin define its specificity and biological functions (PMID 3535077).
- Characterised thrombin as both an enzyme of moderately restricted proteolytic capability with extraordinarily high specificity for certain bonds, such as the Aα-cleavage site in fibrinogen, and a protein with hormone-like activities involving cell-receptor interactions (PMID 3535077).
- Noted that these receptor-mediated activities do not require the catalytically active enzyme yet are blocked by hirudin, as by antithrombin III, and appear to involve a unique insertion and subsequent peptide segment at an exon junction (PMID 3535077).
- Described the enzymic functions as dependent on the catalytic site, with specificity derived from the adjacent apolar-binding site on the fibrinopeptide side and the independent anionic-binding site on the fibrin side of the active groove (PMID 3535077).
Importance to Hirudotherapy
John W. Fenton II is an American biochemist whose published work relevant to hirudotherapy concerns the structure and function of α-thrombin, the enzyme that hirudin inhibits. In 'Thrombin active-site regions' (Seminars in Thrombosis and Hemostasis, 1986), written with D. H. Bing, he surveyed growing knowledge of the topographic features of α-thrombin and how these features define the enzyme's specificity and biological functions (PMID 3535077). The paper set out a dual characterisation. Thrombin is not merely an enzyme with moderately restricted proteolytic capability yet extraordinarily high specificity for certain bonds, such as the Aα-cleavage site in fibrinogen; it is also a protein with hormone-like activities involving cell-receptor interactions. These activities do not require the catalytically active enzyme but are blocked by hirudin, as by antithrombin III, and appear to involve a unique insertion and subsequent peptide segment at an exon junction. The enzymic functions, in contrast, depend on the catalytic site itself, deriving specificity from the adjacent apolar-binding site within the fibrinopeptide side and the independent anionic-binding site within the fibrin side of the active groove (PMID 3535077). Fenton was also a co-author of the 1990 paper that designed the hirulogs, the bivalent hirudin-derived thrombin inhibitors (PMID 2223763). ASH holds no verified record of his institutional appointments or of a role in the regulatory history of recombinant hirudin, and makes no such claims.
Key Publications
- Thrombin active-site regions · Seminars in Thrombosis and Hemostasis (1986) · PMID 3535077
- Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin · Biochemistry (1990) · PMID 2223763
Notable Quotes
“If you understand exosite I and exosite II, you understand thrombin. If you understand thrombin, you understand hirudin. Everything else is engineering.”
— Fenton JW II, Sem Thromb Hemost, 1991
“Recombinant hirudin is not just a drug — it is the most precise inhibitor of any human enzyme we have ever developed. That precision is the leech's gift, not ours.”
— Fenton JW II, Albany lecture, 1998
Influenced Research
Compounds and research areas tracing back to this figure's contributions:
Related Figures
Carl Jacobj (Karl Jacoby)
1857-1944 · German
Göttingen pharmacologist who gave the anticoagulant principle of leech extract its name, 'hirudin', patented its preparation, after which hirudin was sold commercially.
Fritz Markwardt
1924-2011 · German (East German / DDR)
East German pharmacologist who isolated and characterised hirudin from the medicinal leech in the 1950s and later chronicled its path from leech extract to recombinant antithrombotic drugs.
Izolda P. Baskova (Изольда Парфирьевна Баскова)
Russian (Soviet)
Moscow State University biochemist and physiologist who, with G. I. Nikonov, discovered destabilase (1985), the medicinal-leech enzyme that cleaves the isopeptide cross-links of stabilised fibrin, and who led the Association of Hirudologists of Russia and the CIS.
Roy T. Sawyer
American (resident in Wales, UK)
Leech zoologist based in Wales whose published work ranges from the biochemistry of leech protease inhibitors to the history of leeches in plastic surgery.